Epidemiological studies suggest that chronic inhalation of cigarette smoke (SM) is associated with increased risk of cancer, heart disease, respiratory infections, and other infections including AIDS. AIDS dementia complex, and transmission of HIV-1 from mother to the offspring. We and others have shown that SM suppresses the immune system, and it has been postulated that many health consequences of SM result from its effects on the immune system, and it has been postulated that many health consequences of SM result from its effects on the immune system. Nicotine (NT) is the most important pharmacologically active substance in SM, and our laboratory was the first to demonstrate that chronic exposure to NT causes immunosuppression similar to SM and arrests T cells in the G0/G1 phase of the cell cycle. More recent data indicate that chronic exposure to NT, although anti-inflammatory, increases the replication and/or dissemination of the influenza A virus and the yeast-like fungus, Cryptococcus neoformans. In addition, while in vitro NT affects some T cell parameters, many in vivo effects of NT may be primarily mediated through the CNS. Immunosuppression by chronic SM or NT is causally related to the impairment of antigen-mediated signaling in T lymphocytes, leading to T cell anergy. Our preliminary results indicate that these anergic T cells exhibit intrinsic activation of protein tyrosine kinases (PTKs), decreased cytokine production including IL-2, and, interestingly, depleted inositol-1,4,5-triphosphate (IP3)- sensitive intracellular Ca2+ including IL-2, and, interestingly, depleted inositol-1/4/5-trisphosphate (IP3)-sensitive intracellular Ca2+ stores. These stores are critical for T-cell function, including antigen/mitogen- induced proliferation and the transport of transcription factors into the nucleus. Our preliminary results suggest that Fyn, a Src-like PTK found in association with T cell antigen receptors (TCRs) and nicotinic acetylcholine receptor (nAChRs), is constitutively activated in T cells from NT-treatment animals. Interestingly, anergic T cells from mice infected with murine AIDS virus have activated Fyn. Based on these data, we hypothesize that a constitutively active Fyn, through depletion of IP3- sensitive Ca2+ stores, affects the emigration of transcription factors from the cytoplasm to the nucleus. Furthermore, NT specifically activates the Fyn associated with nAChRs leading to a "partial" state of T cell activation resulting in T cell anergy. These studies will help in elucidating the molecular mechanism for immunomodulation by neuro- and immuno- active drugs of abuse. Additionally, the results may provide insight into the mechanism of T cell tolerance and neuroimmune interactions.